Introduction
Long-term treatment of chronic inflammation after ileal pouch-anal anastomosis (IPAA) remains difficult. While biologics are widely used, real-world data on their persistence and the factors that prompt discontinuation are scarce.
Aims & Methods
We aim to describe long‑term use of bioloics as first- and advanced-line therapies, and identify predictors of discontinuation. Patients post-IPAA were prospectively followed in a comprehensive pouch clinic at a tertiary referral center. Inclusion: patients initiating biologics for chronic pouch phenotypes, specifically chronic pouchitis and Crohn's like disease of the pouch. Exclusion: biologics initiated with an existing ileostomy or for extra-intestinal manifestations. Primary outcome: drug persistence. Treatment courses were further divided into first-line and advanced-line therapies. Clinical and endoscopic remission was assessed at 26 weeks in available patients, using the corresponding PDAI subscores. Kaplan-Meier curves, log-rank tests, and Cox models were used to analyze discontinuation-free survival. A recurrent-event Cox model assessed persistence across multiple lines of therapy.
Results
Of 186 patients post-IPAA, 38 patients (21 [55%] females, median 16.8 y post‑IPAA) initiated biologics with overall 63 treatment courses: adalimumab (33.3%), infliximab (26.9%), ustekinumab (25.4%), vedolizumab (6.3%), upadacitinib (4.8%), risankizumab and golimumab (1.6% each). Median biologics overall persistence was 686 days (IQR 210‑1,702). Most treatment courses (34/63, 54%) were discontinued, mainly for primary non‑response (41%), immunogenicity (15%), or adverse events (15%).
In first‑line biologics, 16/38 (42%) patients had persistent therapy at last follow‑up. Week‑26 clinical remission was achieved by 19/21 patients (90%) and endoscopic remission by 5/10 (50%).
Predictors of earlier discontinuation of first-line biologic were: biologics initiation ≤ 5 years post-IPAA (HR 2.46, 95 % CI: 1.13‑5.97), reuse of a biologic administered pre‑IPAA (7/7 failures; HR 3.41, 1.33‑8.76) and female sex (male sex protective; HR 0.30, 0.10‑0.92). All patients of Arab‑ethnicity (5/5, 100%) discontinued therapy (p=0.05). Concomitant antibiotics (17/38, 45%) or immunomodulators (6/38, 16%) did not affect persistence. Anti-glycan antibodies developed in 4 patients (10.8%), and all discontinued biologics. All patients with NOD2 or IRGM homozygous variants discontinued biologics as well.
After first‑line failure, 15/38 (39.5%) patients underwent 25 advanced‑line courses; each additional treatment line doubled the discontinuation hazard (HR 2.48, 95% CI: 1.26‑4.90), while prior therapy duration did not predict future persistence (p=0.5). Ustekinumab accounted for 12/25 courses (48%) and showed the highest persistence rate (63.6%), whereas vedolizumab (n=3), upadacitinib (n=2) and risankizumab (n=1) were universally discontinued.
Conclusion
In patients post-IPAA with phenotypes of chronic pouch inflammation, biologics achieved high short‑term efficacy, including clinical and endoscopic remission. Clinical and surgical factors independently predicted earlier treatment discontinuation. In advanced-line therapies, treatment success declined with each subsequent treatment line. Ustekinumab demonstrated the highest persistence regardless of treatment line. This raises the possibility of a valuable rescue option even after prior biologic failure. These findings call for improved approach to biologics selection in pouch-related inflammatory conditions.
Disclosure
Jacob E Ollech: Has received grant support from Pfizer, consulting fees from Takeda, and
speaker fees from Abbvie, Janssen, Pfizer, Takeda, Novartis, and Bristol Myers Squibb.
Iris Dotan: consultation fee or honorarium from: Abbott, Abbvie, Athos, Arena, Altman
Research, Cambridge Healthcare, Celltrion, Celgene/BMS, Eli-Lilly, Ferring, Falk Pharma, Food
Industries Organization, Gilead, Galapagos, Iterative Scopes, Integra Holdings, Janssen,
Neopharm, Pfizer, Rafa laboratories, Roche/Genentech, Sangamo, Sublimity, Sandoz, Takeda,
Wildbio. Grants: Altman Research, BMS, Pfizer